Thursday, 4 April 2013

STREAMS TRIAL: stem cells in rapidly evolving active MS

#MSBlog: Are you interested in an MS stem cell trial? This one may be for you.

The STREAMS (Stem cells in Rapidly Evolving Active Multiple Sclerosis) trial started recruiting last month – a lot of interest was generated in 2011 when it was first announced that Dr Paolo Muraro, Clinical Reader in Neuroimmunology at Imperial College London, had been awarded a grant from the UK MS Society and UK Stem Cell Foundation to conduct a trial of mesenchymal stem cells in MS.We invited Dr Muraro to answer a few questions: Prof G: "What is this trial aiming to show?" PM: "We are using autologous (a patient’s own) mesenchymal stem cells (MSCs) normally found in the bone marrow to see if giving them back intravenously after growing them in the laboratory can prevent inflammation and perhaps even help repair the nervous system. The patients will be monitored both clinically and radiologically (MRI) after enrolment throughout the duration of the trial. All patients will receive their MSCs but whilst some will receive them at the outset, others will receive theirs 6 months later. The sequence of treatment is “double blinded” – neither patients nor doctors will know in which order the active stem cell product or the dummy product are infused. Although this trial is small, only aiming to recruit 13-15 patients over the next 12 months, we will be contributing to an international effort in which results from about 15 centres are combined to give, what should be, statistically meaningful outcomes." Prof G: "Which patients are you trying to recruit?"PM: "Although the trial will look at all 3 types of MS to include relapsing-remitting, secondary progressive and primary progressive, the inclusion criteria are very restrictive and the key one requires the presence of an active inflammatory lesion on a MRI scan. This scan needs to be very recent and actually within 3 months of any planned bone marrow harvest. As you can imagine, this means that the majority of patients we will be able to recruit will have either relapsing-remitting or early secondary progressive MS. These patients will also require a moderate-severe relapse in the last 18 months. Other relevant criteria include being between 18-50 years old (inclusive), having had a formal diagnosis – not symptoms - of MS of between 2-10 years from entering the study and an EDSS score of between 3.0 - 6.5. Although we are not limiting the trial to London residents and it is open to MS patients within the UK who are registered with the NHS, patients will have to think quite carefully if they live a significant distance from London – the travel expenses allowed will not cover such costs."Prof G: "Why has it taken so long for this trial to start from when it was initially announced by the MS Society?" PM: "As with any clinical trial there are many regulatory bodies to satisfy before the trial gets the go-ahead. In the case of our trial involving mesenchymal stem cells, there were additional requirements. We had to obtain ethics approval from the Gene Therapy Advisory Committee (GTAC), and from the Medicines and Healthcare Regulatory Agency (MHRA) as an Advanced Medicinal Therapeutic Product, and each required extensive documentation, before finally being approved by our local NHS Trust. It’s certainly been a long process but it should be reassuring for patients to know that the trial has gone through some very rigorous assessments. In addition to the regulation, the practical experience is also reassuring: MSCs have been given before for a number of different disorders and seem very safe." Prof G: "It was initially reported that you had identified enough participants – can patients still contact you if interested in this trial?"PM: "When the research funding was first announced and major media including the BBC reported about our study, there was such high interest that we were inundated and nearly overwhelmed by the many enquiries and referrals received. Yet at that stage, we could only register interested people. After all required permissions for the trial were received, we contacted everyone who had confirmed their interest in the trial and found, unfortunately, most were ineligible as they did not fulfil (or no longer fulfilled) all the criteria. We have therefore opened up the trial to any new interested participants who may fulfil these criteria. The study will aim to recruit the participants over the next 12 months." Prof G: "What is the process that a MSer needs to go through to get recruited?" PM: "The first step would be to email stemcellms@imperial.ac.uk – a member of the research team will then contact the patient requesting more information. If the basic criteria appear to be met, we will invite the patient to our NHS clinic initially to discuss the situation and the trials available to them – for this though, we would need a referral from the patient’s GP or Neurologist. If suitable for STREAMS, we would then invite the patient to a screening visit – this is when the trial starts for the patient. The full schedule of visits over the course of the next 12 months is detailed in the patient information sheet."The following is the latest patient information sheet for the STREAMS study.

INCLUSION CRITERIAPatients with clinically and radiologically active multiple sclerosis as defined by: 1. Diagnosis of MS: a. Relapsing remitting MS (RRMS) Either: ≥1 moderate-severe relapse and ≥1 gadolinium enhancing lesion (GEL) in past 18 months Or≥1 moderate-severe relapse and ≥1 new T2 lesion in past 18 months.b. Secondary progressive MS (SPMS) Either With an increase of ≥1 EDSS point (if baseline EDSS ≤ 5.0) or 0.5 EDSS point (if baseline EDSS ≥5.5), in the previous 18 months and ≥1 GEL in past 18 months Or≥1 moderate-severe relapse and ≥1 new T2 lesion in past 18 months.c. Primary progressive MS (PPMS) patients with positive oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF)Require both an increase of ≥1 EDSS point (if base-line EDSS ≤ 5.0) or 0.5 EDSS point (if baseline EDSS ≥5.5), or quantifiable, objective evidence of equivalent progression in the previous 18 months And≥1 GEL in past 18 months or ≥1 new T2 lesion in past 18 months. 2. Age 18 to 50 years. 3. Disease duration 2 to 10 years from diagnosis (inclusive).4. EDSS 3.0 to 6.5 at screening evaluation. 5. ≥1 GEL on MRI within 3 months prior to harvesting. EXCLUSION CRITERIA 1. RRMS without at least one severe relapse in the previous 18 months or without at least one GEL or one new T2 in the previous 18 months. 2. SPMS without relapses and without new lesions (GEL or T2 positive) on MRI in the last 18 months. 3. PPMS without positive CSF OCBs or without a GEL or new T2 lesion in the previous 18 months. 4. No gadolinium enhancing lesion(s) in the 3 months prior to bone marrow harvesting. 5. A previously ineligible patient who failed to meet the MRI requirements of the inclusion criteria will not be reviewed again even if further imaging, revealing ≥1 GEL, becomes available. 6. Failure of BM sample to generate MSCs suitable for clinical use within a specified time frame. 7. Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, within the last 3 months. 8. Treatment with interferon-beta or glatiramer acetate within the last 1 month. 9. Treatment with alemtuzumab (campath-1H) within the last 2 years. 10. Prior treatment with total lymphoid irradiation and autologous or allogeneic hematopoietic stem cell transplantation. 11. Participation in clinical trials of any experimental drugs in the 6 months before study entry. 12. Corticosteroid treatment in the previous 30 days. 13. Presence of any active or chronic infection. 14. Previous history of a malignancy other than basal cell carcinoma of the skin and carcinoma in situ that has been in remission for more than one year. 15. Severely limited life expectancy by any other co-morbid illness. 16. Abnormal blood counts, a history of myelodysplasia or other cytopenia. 17. Known pregnancy, positive urine pregnancy test at screening or risk or pregnancy (this includes patients who are unwilling to practice active contraception for the duration of the study). 18. Any breastfeeding woman. 19. Contraindication to MRI including but not limited to intracranial aneurysm clips (except Sugita), history of intra-orbital metal fragments that have not been removed by an MD (as confirmed by orbital X-Ray), pacemaker and non-MR compatible devices (e.g. heart valves, inner ear implants), history of claustrophobia or the inability of the subject to lie still on their back for a period of 1.5 hours in the MRI scanner. 20. An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or history or presence of renal impairment (e.g. serum creatinine clearance less than 30ml/min). 21. Inability to give written informed consent/comply with study procedures. 22. Any significant organ dysfunction or co-morbidity that the Investigators consider would put the subject at unacceptable risk by participating in the study or that would interfere with the functional assessments. Information about the Principal Investigator for the STREAMS trial:Paolo A. Muraro, MD, PhD is Clinical Reader and Head of the Clinical Neuroimmunology Group at Imperial College London.

Dr Muraro's research is aimed at improving the biological understanding and developing effective therapies for inflammatory neurological diseases, with focus on multiple sclerosis (MS). His programme is funded by the Medical Research Council, the UK Multiple Sclerosis Society, the UK Stem Cell Foundation, the Wellcome Trust and the Italian Multiple Sclerosis Society. He is Chair of the Autoimmune Disease Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR; the largest organization of hematopoietic cell transplantation and cellular therapy research worldwide), University of Wisconsin, USA; is a Member of the UK Multiple Sclerosis Society Research Strategy Working Group and of the Scientific Committee of the Italian Multiple Sclerosis Foundation (FISM). His proposal for a randomised, double-blind crossover trial of mesenchymal stem cells in Multiple Sclerosis (STREAMS) was awarded £525K in 2011 by the UK MS Society and the UK Stem Cell Foundation. For this trial, he leads a team of distinguished co-investigators and collaborators that include Dr Richard Nicholas (Consultant Neurologist, Imperial College Healthcare NHS Trust), Professor Francesco Dazzi (Professor of Stem Cell Biology, Imperial College), Professor David Miller (Professor of Clinical Neurology at the Institute of Neurology, UCL and a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, London), Professor Siddharthan Chandran (Professor of Neurology, University of Edinburgh) and Dr Omar Malik (Consultant Neurologist, Imperial College Healthcare NHS Trust).

Thanks for your comment. Our trial will last 3 years in total. Since it is part of an international trial consortium, however, the results from all other similar trials running in different countries will have to be pooled for joint analysis. The results will be "unblinded" for analysis when patient number 160 (cumulatively from all patients recruited in the national trials) completes their 12 month follow-up visit. I can only venture a guess as to when this will happen, as it all depends on patient recruitment over the next 12-18 months. At present my best estimate is that the first results will become available in 2016.

I know many MS, etc. patients who have benefited from autologous (one's own) stem cell therapies. This should not be news. It is a sad state of affairs that the FDA has recently imposed this unlawful, arbitrary, purposefully vague, undue "minimally manipulated" burden upon doctors offering autologous stem cell therapies... in order to protect the profits of the pharmaceutical companies... as the FDA has already admitted in court. Can you say, "REGULATORY CAPTURE?!!!" People are suffering and/or dying needlessly. What the FDA has done is a crime against humanity -- a genocide of the disabled... sound familiar to any history geeks out there???

This sounds like a waste of time. Mesenchymal stem cells do not enter the brain though blood supply, and there is no evidence that they can fix damage. At best you may get an improvement in blood inflammation markers but it's misleading to think that mesenchymal stem cells will repair damage to CNS.

The current and emerging DMTs hold more promise than this idea. A waste of money, if you ask me.

I wonder if the last poster works for the drugs industry?!Mesenchymal stem cells don't need to enter the brain to have effect and it's more than just an idea. Clinical trials using these cells for other conditions have shown a lot of promise.But there's no patent available on your own stem cells....

Not true that we are "doomed" anonymous, Karussis et al did a study called "Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis". Arch Neurol, 2010. 67(10): p. 1187-94. The secondary progressive patients had improvements even with small doses. I am active in patient organization for expanded stem cell availability in the US.

Dr Muraro, what will the dose of MSC be? Prochymal uses 600 mill-1200 per dose in GVHD, with refractory patients getting up to 8 infusions. Since the goal in that disease is also modulation will you be using doses in similar amounts?

I notice also the Prochymal dose for Crohn's is smaller varied by body weight with two doses of either 2 million cells /kg at the low end but the high dose of 8 mill cells per kg worked better with all patients responding by 28 days. That's still 140 million cells for a 70kg person at the low end and 560 at the high end as a dose for an "attack" of Crohn's.

The MS studies on expanded cells have used really small doses. Example Connick et al used about 100 mill cells in one intrathecal dose--but that leaves the peripheral immune system un modulated doesn't it? Patients had some positive responses in spite of low numbers.

And Bonab et al used just 29 million intrathecally with no IV for modulation then checked on people up to a year. I worry that too small doses may give a poor representation of what the therapy can really do for people.

For me an SPMS person this is the hope for regeneration of damage from years of ongoing disease. I know people who've done well with therapy from countries that allow it, but it's a wild west out here with all kinds of different therapies offered. It's good some serious study is happening. Thanks for the effort.

Also Dr Muraro I wonder about making MRI activity and endpoint. Dr Ebers has made a very strong case that relapse/MRI lesion activity are unrelated to long term disease and disability. Scalfari et al 2010 documented that relapses in year 3 and beyond are inversely related to disability: more relapses in later years means less disability.

What if MSC home in to lesion areas to heal and create gd enhancement while repairing/regenerating the areas? Since you don't have a functional endpoint then using the unvalidated surrpogate marker of gd enhancement as signal about efficacy threatens to allow a type 2 error.

It would be very easy to fool ourselves. I fear delaying a truly helpful and regenerative therapy because we miss the fact that MSC homing may be visible on MRI. The MSC study in Iran noted increased MRI activity but better function in patients... I'll take better function over a pretty MRI any day

"more relapses in later years means less disability"This may be that if you are still having relapses you still have enough nerves for a relapse to be clinically eloquent so you will tend to be less disabled anyway. Also George Ebers is making his case with reference to the old DMTs, I suspect it won't be the case when the long term data comes in for the newer, more effective DMTs. We'll see.Bottom line is, if you don't try, you'll never know.

Marie, the dose in our trial is 2 millions cells /kg body weight, given intravenously once during the trial. I agree that larger or repeated doses could potentially be more effective but (A) they have not shown to be safe in MS and in any trial it is always more prudent to start with a lower dose and (B) generating larger doses of clinical grade autologous (=the patient's own) MSC is not presently feasible with the available funding and facilities.

Please note that Connick et al. gave the MSC intravenously, not intrathecally.

Regarding your points on MRI, they are good points. In addition to the points made by the Mouse Doctor2, the challenge is to be able to show an effect of the treatment over a short period of time. MRI is good at that and it dose give some indication over function the long term although it is true that function is what really matters.

Marie, the dose in our trial is 2 millions cells /kg body weight, given intravenously once during the trial. I agree that larger or repeated doses could potentially be more effective but (A) they have not shown to be safe in MS and in any trial it is always more prudent to start with a lower dose and (B) generating larger doses of clinical grade autologous (=the patient's own) MSC is not presently feasible with the available funding and facilities.

Please note that Connick et al. gave the MSC intravenously, not intrathecally.

Regarding your points on MRI, they are good points. In addition to the points made by the Mouse Doctor2, the challenge is to be able to show an effect of the treatment over a short period of time. MRI is good at that and it dose give some indication over function the long term although it is true that function is what really matters.

I agree with anonymous - I don't know how much longer I will be able to walk I just wish that being from Canada - we ,with a great medical system would start implementing some of the research being done- we seem to always lag behind others - even though it seems that discovery of possible relief for MS sufferers can be partially be accredited to our own doctors & researchers. I would very much like to take part in any trials, but the only way to do so is to go outside of Canada at my expense

My father has secondary progressive and is 59. I hope with all my heart some of these areas of research lead to treatments and potentially undoing the horrendous effects this condition has on the body. My father was an intelligent and gifted engineer and now is a man who is rapidly losing hope and the will to live. I desperately don't want to lose him. I hope this study gives new hope to people like my dad

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